Method of forming carboxylic amino acids



Patented Oct. 30, 1945 METHOD OF FORMING CARBOXYLIC AMINO ACIDSFrederick C. Bersworth, Verona, N. J assignor to The Martin DennisCompany, Newark, N. J a corporation of New Jersey No Drawing.Application July 3, 1941, Serial No. 400,967

4 Claims.

This invention relates to organic chemistry and more particularly tocarboxylic amino acids and has for its object the provision of animproved method of synthesizing such acids.

Another object is to provide a method of forming the alkali metal saltsof the mono and poly carboxylic amino acids of ethylene diamine, and ofother primary, secondary and tertiary amines and polyamines,particularly those of the aliphatic series of amines.

Other objects and advantages will be apparent as the invention is morefully hereinafter disclosed.

Heretofore in the art many difierent methods have been proposed for thesynthesis of carboxylic amino acids. Each of these prior methods havebeen characterized by an exceedingly I low yield of the amino acid.

In general the prior art methods produce as a final product an alkalimetal salt of the carboxylic amino acid in an aqueous solution fromwhich the amino acid is recovered by precipitation on acidification ofthe solution with strong mineral acid.

I have discovered that the exceedingly low recoveries of the amino acidfrom an aqueous solution of the alkali metal salts of said amino acidsupon acidification of the solution with mineral acids is due to the factthat the amino acid, while of relatively low solubility in pure water,has a relatively high solubility in water containing any dissolvedorganic and inorganic compounds, reacting therewith to form complexreaction products which are in the main highly soluble andnon-isolatable therefrom by the ordinary precipitation agents for eitherthe amino acid or the organic and inorganic compound reacted therewith.

After considerable research and experimentation I have arrived at theconclusion that all carboxylic amino acids and th water soluble saltsthereof, in aqueous solution and even in pure water, exist in two forms,molecular and ionic, and that the specific equilibrium between the twoforms in any given solution depends upon the concentration of the acidor its water soluble salt in the solution and the temperature of thesolution.

I have also discovered that the amino acid or salt when ionizedundergoes an internal rearrangement forming an amphoteric complex whichis highly reactive towards acidic and basic ions in solution therewithto form complex compounds therewith which have a high solubility inwater and which subsequently are difficultly decomposable or isolatablefrom solution.

I have further discovered that in any given aqueous solution of a watersoluble salt of the said amino acids, such as for example, in an aqueoussolution of an alkali metal salt of the said acid, the pH of thesolution markedly effects the degree or extent of ionization of thecarboxylic group of said salt and that to substantially suppressionization of the carboxylic group in such solutions the pH of thesolution must approximate at least a pH of about 9.

The discoveries of the chemical characteristics of the said carboxylicamino acids hereinabove described oifer unusual and exceptionalpossibilities of adaptation in the synthesis of these carboxylic aminoacids and in the conversion of the synthesized acids to compounds ofgreat utility in the art. The present invention is directed to a methodof synthesizing the carboxylic amino acids and the formation of thealkali metal salts thereof in aqueous solution.

In co-pending application Serial No. 372,574 filed December 31, 1940, Ihave described a method of forming a condensation product by reacting analdehyde, such as formaldehyde, with a metal cyanide, such as sodiumcyanide, in an aqueous solution under controlled temperature conditions.The condensation product formed in this reaction is a nitrile having acomposition indicated by the formula NaOCHzCN. This nitrile isessentially unstable and undergoes hydrolysis in aqueous solution, therate of hydrolysis increasing with increase in temperature abovetemperatures approximating 30 C. and with decrease in concentration, toa carboxylic acid salt with liberation of ammonia (N H3) The exactmechanism by which this reaction occurs is not apparent and in solutionshaving a pH below about 9 the formation of the carboxylic salt isobscured by reason of the fact that the carboxylic acid salt and theammonia liberated enter into recombination with the remaining nitrilecompound to form a complex system of intermediate reaction products, thecompositions of which are unresolvable by analysis methods known at thepresent.

However, I have found that at a pH above about 9 the conversion of thenitrile to the carboxylic acid salts may be effectively stabilized andrendered substantially complete, but due to the chemical activity of thecarboxylic acid salt formed various condensation products thereof willbe obtained, the precise system of condensation products dependingmainly on the tempera-- ture of hydrolysis and the concentration of thesolution.

As an example, when one mole of formaldehyde (CI-I20) is added slowly toa mole solution of NaCN in about 250 c. c. water, and the temperature ofthe solution is maintained throughout the aldehyde addition at atemperature within the range 15 to 25 C., the aldehyde and cyanide willreact substantially completely to form one mole weight of the nitrilecompound NaOCHzCN. At temperatures below about 30 C. this nitrilecompound is fairly stable for prolonged time intervals in aqueoussolution, the stability of the nitrile increasing with increase in pH upto a pH of about 8. Above a pH of about 8 hydrolysis proceeds slowly attemperatures below about 30f C., but increasing with increase intemperature and with increase in pH. At a pH of about 9 and at alltemperatures above about 30 C. the rate of hy-,

drolysis of the nitrile to the carboxylic acid salt is relatively rapidand at a temperature approximating 60 0., the rate of hydrolysis is sorapid that hydrolysis occurs in a matter of seconds rather than hours asat a, very low pH. i

I have found that in order to inhibit ionization and secondaryhydrolysis of the hydrolysis product the pH of the solution must bemaintained at a pH of at least 9 with alkali hydroxide, the alkali metalof which is identical to the alkali metal constituent of the nitrile.

By permitting the hydrolysis reaction to proceed at a temperature ofabout 40 to 45 C. at a pH below about 9, the resulting hydrolysisproduct is comprised of a system of compounds consisting of a, mixtureof glycine and organic compounds consisting of intermediate reaction anddecomposition products of glycine, the amount of glycine presentapparently decreasing directly with decrease in pH. At a, pH of about 9the formation of glycine appears to be in major 'part inhibited due, itis believed, to the fact that at a pH of about 9 and in the presence ofa strong alkali such as NaOH, the solubility of the ammonia (NHa)liberated in the hydrolysis of the nitrile in the solution isexceedingly low and the bulk of the ammonia (NI-h) is thrown out of thesolution as gaseous or molecular ammonia. By providing means to rapidlyexpel the ammonia from the solution, as by vigorous agitation, higherhydrolysis temperatures or reduced pressures, theformation ofintermediate reaction products by reaction with the NH; liberated duringhydrolysis may be reduced to an extremely low order.

However, I have found that by maintaining a pH above about 9 in thesolution the formation of ammonia reaction products is in major partinhibited and that all such ammonia reaction products formed may besubstantially decomposed by subjecting the solution to prolonged heatingat temperatures approximating the bolling point of the solution.

The discoveries hereinabove disclosed are particularly applicable in thesynthesis of carboxylic amino acids by hydrolyzing the nitrile in thepresence of an amine, such as ethylene diamine,

' as described in the above identified application.

In accordance with the method disclosed therein the nitrile solution isadded slowly to an amine solution which is maintained at a temperaturewithin the range 40-45 C., the rate of addition of the nitrile beingconsistent with the rate of NH: evolution from the solution.

In accordance with this method of synthesis of the carboxylic aminoacid, the temperature of the amine solution is maintained substantiallyconstant and the concentration of the nitrile in the amine solution ismaintained within close limits by controlling the rate of addition ofthe nitrile solution with respect to the rate of nitrile hydrolysis asevidenced by the NH: evolution. Under such carefully controlledconditions a, consistently high percentage conversion of the nitrileinto the carboxylic acid salt and the substitution of this carboxylicacid salt for one of the amino hydrogens of the amine may be obtained,and by so hydrolyzing and substituting up to a total of four (4) molesof the nitrile in an aqueous solution containing one (1) mole ofethylene diamine, the mono-, di-, triand tetrasubstituted carboxylicamino acids may be synthesized.

As an improvement of this process, however, I have found that by addingto the amine solution a suflicient amount of caustic alkali (NaOH) loinsure a pH of above about 9 in the solution during the hydrolysis andsubstitution reaction, the

' hydrolysis reaction is rendered more rapid and more complete; solutionand ionization of the NH: evolved in the hydrolysis reaction issubstantially inhibited; the expulsion of the gaseous ammonia from thesolution is assured; and that the excess alkali stabilizes and inhibitsionization and decomposition of the carboxylic acid group prior to andafter substitution of the same in the amine. By such an alkali additionthe losses incident to the formation of complex intermediatedecomposition and reaction products of the nitrile, the carboxylic acidsodium salt hydrolysis product, and the desired carboxylic amino acidsodium salt reaction product, are greatly minimized and the synthesisreaction results in a relatively high yield of the sodium salt of theparticular carboxylic amino acid being formed, particularly where theconcentration of the amino acid salt in the solution is relatively high.

As a further improvement on the synthesis method disclosed in saidco-pending application, I have discovered that by forming the nitrile,hydrolyzing the same and reacting the hydrolyzed product with an amine,such as ethylene diamine, substantially simultaneously in a solutionhaving a pH above about 9, the reaction can be conducted at materiallyhigher temperatures than 40-45" C. and may be completed in 'a relativelyshort time interval with consistently high recoveries approximating a100% conversion of the amine to the carboxylic amino acid sodium salt inconcentrated solutions.

As an example of this reaction, one mole weight of NaCN and one moleweight of ethylene diamine are dissolved in about 250 0.0. of water andthe solution is brought to a pH of about 9 by the addition thereto ofabout 5 grams of NaOH. The solution is heated to a temperatureapproximating 60 C. and one mole of an aldehyde, such as formaldehyde,is added at a. substantially constant rate while the solution is beingsubjected to vigorous agitation. Preferably the surface of the solutionduring the aldehyde addition is enclosed by a reflux condenser to reducethe losses by volatilization of the aldehyde and preferably also thegases passing through the condenser are collected in an NH: absorptiontower and the ammonia content thereof determined as a check on theprogress and efiiciency of the reaction.

In performing the carboxylic amino acid synthesis reaction in thismanner, the hydrine formed by the condensation of the aldehyde with thecyanide is substantially instantaneously hy drolyzed to the carboxylicacid salt which is substantially instantaneously reacted with the amineto be substituted therein for one of the amino hydrogens thereof.

By regulating the rate of aldehyde addition to the solution to a rateconsistent with the rate of substitution of the carboxylic acid salt inthe amine, limiting the concentration of the carboxylic acid salt to a.relatively low percentage, the method becomes smoothly operative.

At a pH of above about 9 and at temperatures above about 50 C. up toabout C., the NaCN and aldehyde react to form the nitrile relativelyrapidly, particularly in the presence of an excess of NaCN. This rate ofreaction decreases as the relative concentration of NaCN and aldehydeapproach equality, however, as the concentration of the NaCN decreasesin solution the ionization increases, thus preventing the condensationreaction irom slowing up inordinately as to rate of reaction.

As the pH above about 9 inhibits ionization of the hydrolysis product,the substitution reaction of this sodium salt in the amine proceeds at arate governed by the temperature and concentration. In general, I preferto slow down the rate of aldehyde addition after approximately 75% ofthe aldehyde has been added to allow for the decrease in the severalrates of reaction.

These series of reactions hereinabove described maybe summarized asfollows:

. temperature about 60 C.

(2) N80 H1. CN+ (pHo)=Na0 0 H2. 0 0 o Na-j-NH;

NaO CH2 COONa+NHr CH: CH: NHa: (3) NaOOC-CHz-NH -CHz-CI-Iz-NHs+NaOH Theresulting solution of approximately 250 0.0. contains the compoundNaOOC-CHa-NH-CHr-CHz-NHz,

aldehyde (CI-I20) to the solution under exactly 50 the same conditionsas hereinabove disclosed, one molar weight of the sodium salt of thedi-carboxylic acid of ethylene diamine may be formed.

In like manner, the tri and tetra substituted carboxylic amino acidsalts may be produced. I have discovered, however, that whereas it iscomparatively easy to form the mono and di substituted amino acids inthis manner in solutions having a pH of about 9, the formation of thetri and tetra substituted amino acids requires a pH oi about 11 toinhibit ionization of the carboxylic amino acid salt. This is believedin part due to the fact that with increasing substitution the normalbasicity of the amine decreases thereby requiring a higher pH tosuppress the increased tendency of the carboxylic acid salt group(COONa) to hydrolyze to an acid group (-COOH) and in turn to break downto an anhydride:

either by reaction with free hydroxyl ions in the solution or bycondensation between the -COOH groups adjacently attached to the sameamino nitrogen according to the following reaction:

The formation of these corboxylic acid groups and carboxylic acidanhydrides by hydrolysis opens the carboxylic amino acids to interactionwith organic and inorganic ions in solution therewith to form complexcompounds that are exceedingly difiicult to remove or to isolate fromthe solution. It is believed apparent that the tendency of the monocarboxylic amino acid salt to so hydrolyze would be less than thetendency of the di-carboxylic amino acid salt and that the tri and tetrasubstituted acids would evidence a greater tendency to so hydrolyze. Byincreasing the DH of the solution with respect to the extent ofsubstitution from a pH of about 9 to a pH of about 11, the hydrolysis ofthese substituted carboxylic acid groups can be substantially inhibitedand the synthesis reaction may be carried to a substantiallyquantitative conclusion.

It is believed apparent to any one skilled in the art that the reactionhereinabove disclosed and described with respect to the formation of thesodium salt of the mono to tetra carboxylic acid of ethylene diamine, isequally as applicable to the formation of any alkali metal salt of saidacid by substituting such alkali metal cyanide and hydroxide compoundsfor the sodium cyanide and hydroxide compounds specified in the amountsand proportions indicated, and in the claims the term sodium cyanide andthe term sodium hydroxide are to be construed as includ- 4o ing, asequivalents therefor, any alkali cyanide or hydroxide.

It is believed apparent to any one skilled in the art that any aliphaticamine such as the primary to tertiary, mono and poly amines may besubstituted for the ethylene diamine of the specific embodiment givenwithout essential departure from the present invention, suchsubstitution requiring only the application of the expected knowledgeand skill of one skilled in the art in the regulation of the solutionpH, temperature and concentration in the ractice of the presentinvention so modified.

As an illustration of the equivalency of such 5 other amines, diaminepropanol having the formula:

CHr-NH:

may be substituted for ethylene diamine in the specific embodimentsabove given and the mono to hexa substituted carboxylic amino acids maybe synthesized therefrom.

Propylene diamine having the formula:

H-NHr may be substituted for the ethylene diamine and the mono to hexasubstituted carboxylic amino acids synthesized therefrom.

Ethylamine (czHa'NHz) may be converted into 7 the mono-, di-, andtri-carboxylic amino acid.

Diethylene triamine having the structure:

([lHr-NH: CH:

Gri

HrNHI l CHz-NH:

may be converted into the mono to hexa (plus two) carboxylic amino acid,the two extra car-- boxylic acid groups displacing the two aminohydrogens of the two center NH groups.

From the above examples, it is believed apparent that in the practice ofthe present invention a plurality of carboi-wlic amino acids of thealiphatic series of amines and poly amines may be synthesized bysubstituting such amines for the ethylene diamine of the specificembodiments hereinabove given and that such amines chemicallyare fullequivalents for the ethylene diamine of the specific embodiments.

It is also believed apparent that any aldehyde may be substituted forthe formaldehyde of the specific embodiment given without essentialdeparture from the present invention, such substitution providing meansfor obtaining a plurality of carboxylic acid groups for substitution inthe amine, thereby giving rise to carboxylic amino acids not heretoforeknown in the art and requiring only the application of the expectedknowledge and skill of one skilled in the art in the" regulation of thesolution pH, temperature and concentration in the practice of thepresent invention so modified.

It is also believed apparent to any one skilled in the art that even inthe practice of the present embodiment given, wide variations intemperature during the hydrolysis and substitution reactions may be madewithout essential departure from the present invention, and that therelative concentrations of the nitrile, the carboxylic hydrolysisproduct and the amine may be widely varied without substantial departurefrom the present invention. In general, the hydrolysis of the nitrilemay be obtained at any temperature within the range 30-l00 C. althoughpreferably the hydrolysis is performed within the range 5075 C. wherethe mole reacting weights are employed in the concentrations given inthe specific embodiment. As the concentration of the mole reactingweights decreases, ionizatlon and reaction rates increase and lowerhydrolysis and substitution temperatures are preferred and vice versa.In general, as the concentration of the sodium salt of the carboxylicamino acid decreases the amount of free caustic alkali in the solutionto inhibit ionization of the carboxylic acid groups present in thecompound increases as one skilled in the art will recognize.

Having hereinabove described the present invention generically andspecifically and given one specific embodiment thereof and identifiedthe substantial equivalents for the reacting compounds of the specificembodiments, all modifications and adaptations of the present inventionare contemplated within the scope of the-following claims.

What I claim is:

1.- The method of forming the alkali metal salts of a mono carboxylicamino acid which comprises forming an aqueous solution containingsubstantially equimolecular weights of sodium cyanide and ethylenediamine, adding sodium hydroxide thereto in an amount at leastsufficient to produce a pH of about 9, heating the solution to a.temperature within the range 50 to 75 C. and adding thereto for eachmolecular weight NaCN originally present therein one molecular weight offormaldehyde, the rate of addition of said formaldehyde being regulatedin proportion to the evolution of NH: formed by the reaction and withrespect to the temperature of heating and the concentration of saidsolution to maintain a. relatively low concentration of the compoundformed by the hydrolysis of the product of reaction between the saidcyanide and said ing substantially equimolecular weights of an alkalimetal cyanide and ethylene diamine, adding an alkali metal hydroxidethereto in an amount at least sufilcient to produce a pH of about 9.heating the solution to a temperature within the range 50 to 75 C. andadding thereto for each molecular weight of alkali metal cyanideoriginally present therein one molecular weight of formaldehyde, therate of addition of said formaldehyde being regulated in proportion tothe evolution of NH3 formed by the reaction and with respectto thetemperature of heating and the concentration of said solution tomaintain a rela tively low concentration of the compound formed by thehydrolysis of the product of reaction between the said cyanide and saidaldehyde in the said solution, and removing ammonia as it forms.

3. The method of forming the alkali metal salts of a mono carboxylicamino acid which comprises forming an aqueous solution containingsubstantially equimolecular weights of an alkali metal cyanide and analiphatic amine, adding an alkali metal hydroxide thereto in an amountat least sufiicient to produce a pH of about 9, heating the solution toa temperature within the range 50 to 75 C. and adding thereto for eachmolecular weight of alkali metal cyanide originally present therein onemolecular weight of Certificate of Correction Patent No. 2,387,735.October 30, 1945.

FREDERICK C. BERSWORTH It is hereby certified that errors appear in theprinted specification of the above numbered patent requiring correctionas follows: Page 3, first column, line 25, strike out (1); lines 27 to31 inclusive, strike out NaO-CIL-COONa NHyCHrCH;-NH:= (3) NaOOC-OH,-NH-CH,-CH,-N HrI-N aOH page 3, second column, line 10, forcorboxylic read carbozylic; page 4, second co umn, line 38, strike outthe period after the numeral 9 and insert instead a comma;

and that the said Letters Patent should be read with these correctionstherein that the same may conform to the record of the case in thePatent Ofiice.

Signed and sealed this 19th day of March, A. D. 1946.

LESLIE FRAZER,

First Assistant Commissioner of Patents.

